Latanoprost is a prostaglandin-type therapeutic agent for glaucoma represented by a chemical name of isopropyl (Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptanoate. Latanoprost is a selective FP receptor agonist and lowers intraocular pressure by promoting outflow of an aqueous humor (See, for example, Japanese Patent No. 2721414). An administration route of latanoprost is instillation, and an ophthalmic solution containing 0.005% latanoprost (trade name: Xalatan ophthalmic solution) is commercially available.
An object of the present invention is to provide better formulations of a latanoprost ophthalmic solution.
As a preservative of the ophthalmic solution, benzalkonium chloride (hereinafter abbreviated as “BAK”) is the most widely used from the standpoint of effects and the like. However, while BAK has an excellent preservative effect, BAK may cause corneal disorders when it is used at a high concentration. Accordingly, when BAK is added to the ophthalmic solution, it is desirable to lower its concentration as low as possible.
BAK described in the specification means a mixture of compounds having a chemical structure represented by [C6H5CH2N(CH3)2R]Cl wherein alkyl (represented by R) is C8H17˜C18H37.
BAK is defined as follows in Japanese, United States and European Pharmacopoeia.
Japanese Pharmacopoeia: BAK is represented by [C6H5CH2N(CH3)2R]Cl wherein R is C8H17˜C18H37 and mainly comprises C12H25 and C14H29.
United States Pharmacopoeia: BAK is a mixture of alkylbenzyldimethylammonium chloride represented by [C6H5CH2N(CH3)2R]Cl wherein R is a mixture of all or some alkyl groups which are higher than C8H17 and mainly comprises C12H25, C14H29 and C16H33.
European Pharmacopoeia: BAK is a mixture of alkylbenzyldimethylammonium chloride wherein alkyl has chain length of C8 to C18.
On the other hand, a tonicity agent is usually added to the ophthalmic solution in order to keep isotonicity and is exemplified by inorganic salts such as alkali metal salts such as sodium chloride and alkaline earth metal salts such as magnesium chloride.
Further, a buffer is usually added to the ophthalmic solution in order to prevent a change of pH and is exemplified by inorganic salts such as sodium phosphate and sodium borate and organic salts such as sodium acetate, sodium citrate and sodium carbonate.
The tonicity agent and the buffer are contained in a commercially available latanoprost ophthalmic solution.
The present inventors prepared and studied latanoprost ophthalmic solutions containing these widely-used additives.
As a result, surprisingly it was turned out that white turbidity is not observed at a BAK concentration of 0.015% or higher, while it is observed at a BAK concentration of 0.01% or lower. That is because hydrophobic latanoprost and BAK form a complex, and the latanoprost-BAK complex is precipitated due to a salting-out effect by salts, i.e. additives. The present inventors discovered the fact, to their surprise, that the complex is not precipitated until the BAK concentration is lowered to 0.01% or lower. Since the commercially available latanoprost ophthalmic solution (trade name: Xalatan ophthalmic solution) contains 0.02% of BAK, a problem of white turbidity is not caused. However, as mentioned above, though BAK is the excellent preservative, it may cause the corneal disorders when used at the high concentration. Accordingly, when BAK is added to the ophthalmic solution, it is desirable to lower its concentration as low as possible.